Send to

Choose Destination
Dis Model Mech. 2014 Jul;7(7):895-905. doi: 10.1242/dmm.015495. Epub 2014 May 8.

The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia.

Author information

Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208, USA.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA.


Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis - a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM-CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA.


AMPK; ATP; ATR; Chk1; Exogenous nucleosides; RNR; Ribosomal protein deficiency; Rpl11; Rps19; p53

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center